Current and future disease-modifying therapies in multiple sclerosis

Abstract

Summary The development of disease‐modifying therapies (DMT) in multiple sclerosis (MS) has rapidly evolved over the last few years and continues to do so. Prior to the United States Food and Drug Administration approval of the immunomodulatory agent, interferon‐β1b in 1993, no other drug had been shown to alter the course of the disease in a controlled study of MS. At present, there are five licenced disease‐modifying agents in MS – interferon‐β1b, interferon‐β1a, glatiramer acetate, natalizumab and mitoxantrone. All have shown significant therapeutic efficacy in large controlled trials. However, current therapies are only partially effective and are not free from adverse effects. Moreover, available DMTs are overwhelmingly biased in favour of those with relapsing‐remitting disease. Effective treatment for progressive MS is severely limited, with only interferon‐β1b and mitoxantrone having licenced use in secondary progressive, but not primary progressive disease. Monoclonal antibodies, such as natalizumab selectively target immune pathways involved in the pathogenic process of MS. Alemtuzumab, daclizumab and rituximab are other notable monoclonal antibodies currently undergoing phase II and III trials in MS. Alemtuzumab has so far shown promising therapeutic benefit in relapsing disease, although immunological adverse effects have been a problem. Oral therapies have the benefit of improved tolerability and patient compliance compared with current parenteral treatments. Cladribine and fingolimod (FTY720) have shown encouraging results in their phase III clinical trials. It is also worth noting the evidence for starting DMT in patients with clinically isolated syndrome, whereby early treatment has shown to delay the onset of clinically definite MS in separate phase III studies.

Fatigue and Cognition in Patients with Relapsing Multiple Sclerosis Treated with Interferon Beta

“…As a result of these mechanisms, one could predict that IFN would improve overall fatigue in MS patients. However, it should be noted that IFN may potentially worsen fatigue and cognitive deficits as a result of influenza-like adverse effects associated with the use of IFN (Lim & Constantinescu, 2010;Mikol et al, 2008). Furthermore, patients receiving IFN reported significant decreases in quality of life for cognitive functioning, and marginally in worse fatigue (Homewood et al, 2003).…”

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

“…Although they are practically entirely aimed at the relapsing stages of the disease where inflammation is a predominant pathogenic mechanism, they have made a major impact (Lim and Constantinescu, 2010b). In the progressive stages of disease, axonal/ neuronal loss partially dissociated from inflammation is more prominent, although low-grade inflammation persists.…”

“…The readers are directed to recent reviews (Lim and Constantinescu, 2010b;Rejdak et al, 2010;Yiu and Banwell, 2010).…”

Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis

“…These sites of inflammation are believed to be initiated by adaptive immune responses directed against antigens derived from CNS myelin, although innate responses play a major role in the evolution of the lesion. Current treatments for MS invariably act without discriminating between pathogenic autoimmune responses and homeostatic immune function, either by inhibiting inflammatory responses, depleting certain classes of immune cells, sequestering immune cells within lymph nodes, or by limiting the access of immune cells to the CNS, with associated risks and side-effects (Lim and Constantinescu, 2010;Benkert et al, 2012;Steinman, 2012). Therapies that are able to selectively disrupt immune responses directed against autoantigens may be able to prevent the development of lesions at an earlier stage, thereby proving safer and less intrusive than treatments which suppress autoimmunity by disrupting systemic immune function.…”